Discussion
The study explored the electrophysiological characteristics and differential densities of KCa3.1 in rabbit atrium and thoracic veins. We offer evidence that (1) the expression of KCa3.1 is higher in the PVs and SVC than in the RA and LA; (2) DAD and DAD-induced triggered activity was induced in the PVs and SVC but not in the RA or LA by electrical stimulation in the presence of isoproterenol and high calcium. The KCa3.1 inhibitor TRAM-34 inhibited DAD and DAD-induced triggered activity in the PVs and SVC. (3) EAD was induced in the PVs and SVC but not in the RA or LA by electrical stimulation in the presence of acetylcholine and high calcium. The KCa3.1 inhibitor TRAM-34 inhibited EAD in the PVs and SVC.
The thoracic veins such as PVs and SVC are important foci for ectopic atrial tachycardia and AF. The PVs cause approximately 70% cases of AF, while SVC as second most important thoracic vein for AF, causes 5.3-12.8% AF.2 It can be easily elicited 3 phase EAD and DAD trigger activity in PVs, SVC preparations by parasympathetic or sympathetic nerve stimulation which indicate that automaticity and trigger activity are related to calcium regulation. 3The mechanism of increased PVs and SVC automaticity remains unclear. Specialized cardiac cells associated with pacemakers, such as P-like and Purkinje cells, have been observed in the PVs and SVC of rats, dogs and humans.12 Cardiac developmental studies have shown that PVs, SVC and sinoatrial nodes originate from venous sinuses rather than cardiac progenitor cells. Researchers have found that these sites are prone to spontaneous electrical activity and that automaticity is significantly increased.13 Studies have shown that KCa3.1 is expressed in the human atrium but is absent in the ventricle, and KCa3.1 is also expressed in the PVs of dogs and rabbits.14,15In the present study, we found that the distribution of KCa3.1 in the heart is heterogeneous and is high in the PVs and SVC but low in the RA and LA. Furthermore, the expression of KCa3.1 was significantly higher in the PVs than in the SVC.
KCa3.1 plays an important role in the automaticity in human embryonic stem cells by shaping diastolic slope during diastolic afterdepolarization. KCa3.1 inhibitor not only significantly decrease or even stop the automaticity of human embryonic stem cell-derived cardiomyocytes but also reduce the sinoatrial node firing rate.8 It has been recognized that DAD and late 3 phasic early afterdepolarization (EAD) in the thoracic vein are the underlying mechanisms of ectopy initialed AF.3Previous study shows that iPSCs derived cardiomyocytes from catecholamin-sensitive ventricular tachycardia patient have more KCa3.1 expressed compared to cardiomyocytes from the normal person, which make it more vulnerable to DAD-induced trigger activity under isoproterenol super-fused. Blockade KCa3.1 by TRAM-34 eliminated the DAD-induced trigger activity.9 In our study, DAD and DAD-induced triggered activity was easily elicited in the PVs and SVC but not in the RA and LA. 5uM TRAM-34 eliminated the DAD-induced triggered activity by selectively blockading KCa3.1. Sympathetic activation increases cardiac calcium entry and spontaneous sarcoplasmic reticulum calcium release, which eventually produces local increases in cytosolic Ca2+ that extrudes via the Na+-Ca2+ exchanger generating cellular depolarization, with DAD, which triggers premature beats and tachyarrhythmia.16 Previous study has shown that after left atrial volume overload, the action potential duration in the pulmonary vein was shortened by the activation of KCa3.1.15 From our previous studies, after 7 h pacing, KCa3.1 is significantly higher in the atrium than the control group. Injection of TRAM-34 could terminate AF and decrease the heart rates. 5 All the evidence above indicates that KCa3.1 is essential for automaticity and trigger activity in PVs and SVC by influencing the DADs and calcium transient.